Prenatal alcohol exposure in humans can result in fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE). Exposure to ethanol in utero is the leading known cause of mental retardation in the United States. The medical and behavioral consequences of prenatal ethanol exposure include depressed IQ, developmental delays, attentional deficits, microcephaly, neurologic abnormalities, and facial dysmorphology. The primary action(s) of ethanol on cells of the developing nervous system are not known. The general hypothesis guiding this work is that ethanol disrupts CNS development by directly altering the normal expression of specific genes, resulting in a cascade of developmental consequences that characterize FAS. This proposal describes one possible model system for testing this hypothesis. Despite the importance of glial cell participation in CNS development their potential role in the etiology of FAS has been largely overlooked. Evidence is presented that brief exposure to ethanol during a period of brain development equivalent to the third human trimester causes a large transient increase in steady-state levels of glial fibrillary acidic protein (GFAP) mRNA and protein in rat cerebral cortex. Experiments are also presented that demonstrate that these increases may be a direct effect of ethanol on astrocytes since a similar dose and duration of ethanol exposure in cortical astrocyte primary cultures results in a comparable increase in GFAP expression. This suggests that an important potential mechanism for ethanol-induced increases in GFAP involves the modulation of transcriptional regulation of astrocyte gene expression. The specific aims o this proposal are (1) to describe the time-course and dose- dependence of ethanol's effects on steady-state levels of GFAP mRNA and protein. The results of these experiments will assess the similarity of astrocyte responses in these two models, and will define conditions for experiments described in specific aim 2, and (2) to directly determine the effect of ethanol on the rate of GFAP transcription in vitro and in vivo. Identification of the mechanism(s) by which ethanol causes these changes in GFAP gene regulation will provide important insights into (i) the action of ethanol on glial cells, (ii) the ways in which ethanol can modulate gene expression in general, and (iii) the physiologic and developmental circumstances under which certain cells are vulnerable to ethanol. Results of these experiments will form the foundation for future experiments central to the long-term goal of this work, to describe the mechanisms underlying ethanol-induced changes in gene expression in astrocytes, and to assess the role of these changes in the etiology of FAS-related CNS abnormalities.